Cyanoacrylate Adhesive Compositions, Methods of Sterilization of the Compositions, and Articles of Manufacture Containing Such Compositions

ABSTRACT

The viscosities of 2-cyanoacrylate adhesive compositions are adjusted by the addition of polymeric thickeners to a preferred initial viscosity that will not increase significantly when sterilized by heating them at a temperature of no greater than about 110° C. for no more than about 120 minutes. Articles of manufacture are vials or squeezable tubes containing these compositions.

PRIORITY CLAIM

This U.S. application for utility patent is a divisional of U.S. patent application Ser. No. 13/358,690 filed Jan. 26, 2012, which is a divisional of U.S. patent application Ser. No. 10/944,635 filed Sep. 17, 2004, now U.S. Pat. No. 8,110,144, granted Feb. 7, 2012.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to compositions of cyanoacrylate monomer and polymer adhesive compositions, a process for sterilizing them for application in the medical and veterinary fields, and a method of assaying the sterilization of cyanoacrylate compositions.

2. Background

It is known to use 2-cyanoacrylate esters as adhesives for bonding tissue in medical or surgical procedures performed upon the human or animal body. 2-cyanoacrylate esters polymerize rapidly, and often instantaneously, upon contact with tissue or body fluid. In these applications, the adhesive composition can be used to close wounds, as well as for covering and protecting surface injuries such as lacerations, abrasions, burns, sores and other open surface wounds. To be used in medical and veterinary fields, 2-cyanoacrylates must be sterilized. This is generally done in sealed containers to provide sterility, and from a practical perspective, to protect the compositions from moisture and premature polymerization. Previous sterilization methods involved either the use of ionizing radiation, including e-beam and gamma ray irradiation, dry heat at elevated temperatures (160° C.), or chemical sterilization such as with ethylene oxide.

When an adhesive composition is applied to a surface to be closed or protected, it is usually in its monomeric form, and the resultant polymerization produces the desired adhesive bond. However, at ordinary temperatures, the monomeric form of the adhesive has a low viscosity which results in the adhesive spreading into undesired areas. Therefore, it is desirable to increase the viscosity of the composition to prevent this unwanted flow. In order to achieve an increased viscosity, thickening agents can be added to the monomeric composition.

The previous methods of sterilization are undesirable in that the high temperatures required for the previous dry heat sterilization processes or irradiation could cause premature polymerization of the monomers. In addition, many polymers that could be used as thickeners underwent degradation resulting in loss of viscosity when exposed to typical dry heat conditions of 160° C. This significantly limits the formulators ability to formulate adhesive compositions which have the desirable stability and flow characteristics, and which can be sterilized.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to a method of sterilizing 2-cyanoacrylate compositions, including heating the composition in a device at a temperature of from about 70° C. to about 140° C. for an effective amount of time. In another aspect, the invention includes sterilized 2-cyanoacrylate ester compositions for use in medicine or surgery, the compositions being disposed in sealed aluminum containers and being sterilized at a temperature of between about 70° C. and about 140° C. The compositions can be disposed in sealed aluminum, tin, stainless steel tubes or pouches or glass containers. Preferably, the 2-cyanoacrylate compositions are adjusted to an initial viscosity of 400 to 600 centipoises by the addition of polycyanoacrylate thickeners, and are sterilized in a preferred method by heating them at a temperature of no greater than about 110° C. for no more than about 120 minutes. Articles of manufacture are vials or squeezable tubes made of compatible glass, aluminum, or plastic.

In yet another aspect, the invention is directed to a method for assaying the sterilization of cyanoacrylate compositions.

DETAILED DESCRIPTION OF THE INVENTION

As embodied and described herein, the present invention provides a novel method of sterilizing 2-cyanoacrylate ester compositions using a combination of chemical and heating means, and the resulting novel compositions. The combination of monomeric 2-cyanoacrylate, heat and time have a lethal effect on microbials, rendering sterilized compositions when the appropriate sterilization condition is achieved and when the method is applied to 2-cyanoacrylates in sealed containers.

As used herein, the following terms have the following meanings:

The term “cyanoacrylate adhesive composition” or “cyanoacrylate adhesive compositions” refers to polymerizable formulations comprising polymerizable cyanoacrylate ester monomers. The term aldose is intended to refer to both common disaccharides and monosaccharides.

In the method of the invention, 2-cyanoacrylate adhesive compositions are sterilized through an unexpected and heretofore unknown combination of heat and time, sterilizing at temperatures significantly lower than previously thought to be effective. Previous dry heat sterilization methods have required temperatures of at least 160° C. to 180° C. Heating times at these temperatures were from 2 hours at 160° C. to 30 minutes at 180° C. Under the present invention, the 2-cyanoacrylate adhesive compositions can be sterilized at temperatures from about 70° C. to about 140° C. As would be expected, the time required to effect sterilization will vary depending on the temperature selected to accomplish the sterilization. At 140° C., sterilization requires approximately 30 minutes. At 70° C., sterilization requires about 600 minutes. Required heating times for intermediate temperatures are reported in Tables 2 and 3. Ultimately sterilization times for any composition can be readily determined by one skilled in the art by standard test methods without undue experimentation.

Typical sterilization times are listed in Table 1.

TABLE #1 sterilization heating times  70° C. 600 minutes  80° C. 480 minutes  90° C. 300 minutes 100° C. 120 minutes 110° C.  90 minutes 120° C.  60 minutes 130° C.  60 minutes 140° C.  30 minutes

According to the assay method of the invention, sterilization of cyanoacrylate compositions can be assayed for the effectiveness of a given temperature and sterilization time. Samples containing formulated n-butyl cyanoacrylate and 2-octyl cyanoacrylate in sealed borosilicate glass and aluminum tubes were inoculated with Bacillus subtilis lyophilized spores at a concentration of 1×10⁺⁶ per ml of formulation. In other embodiments, spores can be introduced into the cyanocrylate adhesive compositions prior to sterilization using commercially available biological indicators or spore test strips. Among the commercially available biological indicators which may be used are: bacterial spores on a stainless steel disc, bacterial spores on a steel wire, bacterial spores on steel coupons, bacterial spores on borosilicate paper and bacterial spores on woven cotton threads. Among the species of spores which may be chosen for use in the commercially available biological indicators are Bacillus subtilis and Geobacillus stearothermophilus. Commercially available biological indicators may be obtained from any commercial supplier, such as Raven Labs. Some inoculated glass vials and tubes samples were kept at room temperature without sterilization as positive controls, while the rest of the samples were sterilized at temperatures ranging from 70 to 140° C. with different time exposures. Samples were sent to a microbiology laboratory for determination of the presence or absence of growth after the sterilization procedure was completed to assay the effectiveness of the process conditions.

In accordance with the present invention it is preferred to utilize microorganisms which may be killed by the sterilization process but which show significant resistance to this process. The term microorganism refers to bacteria, fungi, yeast, protozoa algae, viruses and protozoa. Bacterial spores are very resistant to heat and chemicals; more so than vegetative bacterial cells, therefore the spores are often used to monitor sterilization procedures. A preferred organism for monitoring dry heat sterilization is Bacillus subtilis.

The spores represent a resting stage in the life cycle of the Bacillus genus. The resting spore contains a large number of active enzymes which allow the transformation from dormant cell to vegetative cell. The germination process, or the return to the vegetative state, has been described as a time-ordered sequence involving activation, triggering, initiation and outgrowth. Activation is reversible and involves an increase in the rate and extent of germination. Triggering is irreversible and is the result of spore contact with the germinant. Initiation involves the loss of heat resistance, release of dipicolinic acid and calcium, loss of refractility and absorbance. Outgrowth results in formation of the vegetative cell.

In accordance with the present invention a cyanoacrylate composition test sample comprising at least one sterility test strip, or lyophilized spores is utilized. While reference is made to “spores” as a test microorganism it should be understood that microorganisms other than spore formers may be used in conjunction with the present invention. The spore strips utilized with the present invention are preferably constructed of materials which are inert to the microorganisms and inert to cyanoacrylate monomer. A variety of commercial spore strips is readily available and can be utilized with the present invention. The spore strips can contain more than one type of microorganism.

To assay the sterilized samples and controls, the compositions including the biological indicators are transferred into containers filled with an aqueous aldose solution, shaken, and transferred into a quantity of nutrient medium in an aseptic container. Transferring the samples to an aldose solution serves to emulsify the cyanoacrylate monomer without causing it to polymerize as it would upon exposure to water alone. Aldoses which act to emulsify the cyanoacrylate include without limitation, dextrose, lactose, arabinose, mannose, galactose, rhamnose, fructose, sucrose and glucose. In one embodiment of the invention, the aldose is dextrose. The concentration of the aldose solution may be from about 2% to about 50% on a weight/weight basis. A preferred range for the concentration of the aldose solution is from about 3% to about 15%. A more preferred aldose concentration is from about 5% to about 10% weight/weight. The nutrient medium supports the germination of spores and growth of any viable microorganisms. The nutrient medium contains a protein substrate for the proteases liberated during spore germination and during subsequent microbial growth. The nutrient medium preferably comprises an aqueous solution or suspension of nutrient components (including the protein substrate) needed in order to promote the growth of viable microorganisms that may exist after the sterilization process. One example of a suitable culture medium is a protein-containing microbiological broth such as tryptic soy broth (TSB) and/or TSB with specific protein additives, such as, for example, casein. Formulations for culture media are well-known to those in the art.

The mixture of microorganisms, cyanoacrylate, aldose and nutrient medium are then sealed within a containing means. The samples are then incubated for a predetermined period of time at from about 28° C. to about 37° C. Any microorganisms not killed during the sterilization process begin to germinate and grow during the incubation period. In a preferred embodiment the microorganisms are incubated for at least about seven days. Thereafter the sample is examined to detect the presence of growth by different methods, such as visual examination of the samples followed by microscope Gram stain examination, addition of an enzymatic indicator such as tetrazolium salts followed by UV spectrophotometric analysis, or direct UV spectrophotometric analysis of incubated samples. In one embodiment, after visual examination a gram stain smear is prepared to look for gram positive rods which would confirm growth. In another embodiment, growth can be determined by the addition of enzymatic biological indicator such as tetrazolium salts, wherein bacterial activity is determined by development of color which may be measured quantitatively with an ultraviolet spectrophotometer at 257 nm. In yet another embodiment, a sample without enzymatic indicator is analyzed under a spectrophotometer at a wavelength of 480 nm to determine growth.

The method of the invention can be applied in principle to any 2-cyanoacrylate ester monomer. The 2-cyanoacrylate is preferably an aliphatic cyanoacrylate ester and preferably an alkyl, cycloalkyl, alkenyl, alkoxyalkyl, fluoroalkyl, fluorocyclic alkyl or fluoroalkoxy 2-cyanoacrylate ester. The alkyl group may contain from 2 to 12 carbon atoms, and is preferably a C₂ to C₈ alkyl ester, and is most preferably a C₄ to C₈ alkyl ester. Suitable 2-cyanoacrylate esters include without limitation, the ethyl, n-propyl, iso-propyl, n-butyl, pentyl, hexyl, cyclohexyl, heptyl, n-octyl, 2-ethylhexyl, 2-methoxyethyl and 2-ethoxyethyl esters. Any of these 2-cyanoacrylate monomers may be used alone, or they may be used in mixtures.

The 2-cyanoacrylate monomers of the invention can be prepared by any of the methods known in the art. U.S. Pat. Nos. 2,721,858, 3,254,111 and 4,364,876, each of which is hereby incorporated in its entirety by reference, disclose methods for preparing 2-cyanoacrylates. For example, cyanoacrylates for the instant invention were prepared by reacting cyanoacetate with formaldehyde in the presence of heat and a basic condensation catalyst to give a low molecular weight polymer. A depolymerization step followed under heat and vacuum in the presence of acidic and anionic inhibitors, yielding a crude monomer that could be distilled under vacuum and in the presence of radical and acidic inhibitors. The distilled 2-cyanoacrylate monomers are then formulated with radical and acidic inhibitors depending upon their application and to provide the necessary stability.

The 2-cyanoacrylate compositions of the invention may in some embodiments contain a thickening agent to increase the viscosity of the composition. This thickening agent may be a polymer. The thickening agent may be selected from the group consisting of without limitation, poly alkyl-2-cyanoacrylates, poly cycloalkyl-2-cyanoacrylates, poly fluoroalkyl-2-cyanoacrylates, poly fluorocycloalkyl-2-cyanoacrylates, poly alkoxyalkyl-2-cyanoacrylates, poly alkoxycycloalkyl-2-cyanoacrylates, poly fluoroalkoxyalkyl-2-cyanoacrylates, polyalkoxycyclofluoroalkyl-2-cyanoacrylates, poly vinyl acetate, poly lactic acid and poly glycolic acid. In order to obtain optimum solubility of the polymer in the monomer, the polymer is often chosen to be a polymer of the monomer or one of the monomers which comprise the 2-cyanoacrylate composition. Preferably, the polymer is soluble in the monomer composition at ambient temperature. Preferred polymers include polymers of octyl 2-cyanoacrylate, vinyl acetate lactic acid, or glycolic acid. The preferred weight average molecular weight of the polymers is from about 300,000 to about 2,000,000. More preferably, the polymer molecular weight is from about 500,000 to about 1,600,000.

Cyanoacrylate polymers of the invention can be prepared by slow addition of the monomer to a mixer containing 0.1% bicarbonate deionized water. Water is then decanted away, and the polymer is rinsed several times with deionized water and decanted again. Following steps include neutralizing the polymer with 0.1 N HCl, rinsing with deionized water, drying on a vacuum heated oven at temperature of less than 80° C. and grinding the polymer to fine particles.

The amount of thickening agent that is added to the monomer composition is dependent upon the molecular weight of the polymer and the desired viscosity for the adhesive composition. The thickening agent typically is added at from about 1% to about 25% by weight of the composition. Preferably it is added at from about 1% to about 10%. More preferably it is added at from about 1% to about 5%. A typical viscosity of the composition is from about 25 to about 3000 centipoises, as measured by a Brookfield viscometer at 25° C. Preferably, the viscosity is between from about 50 to 600 centipoises at 25° C. The specific amount of a given thickening agent to be added can be determined by one of ordinary skill in the art without undue experimentation.

The 2-cyanoacrylate compositions may contain one or more acidic inhibitors in the range from 1 to 1,000 ppm. Such acidic inhibitors include without limitation: sulfur dioxide, nitrogen oxide, boron oxide, phosphoric acid, ortho, meta, or para-phosphoric acid, acetic acid, benzoic acid, cyanoacetic acid, tri-fluoroacetic acid, tribromoacetic acid, trichloroacetic acid, boron trifluoride, hydrogen fluoride, perchloric acid, hydrochloric acid, hydrobromic acid, sulfonic acid, fluorosulfonic acid, chlorosulfonic acid, sulfuric acid, and toluenesulfonic acid.

The 2-cyanoacrylate compositions may contain one or more free radical polymerization inhibitors in the range from 0 to 10,000 ppm. Examples such radical inhibitors include, without limitation, catechol, hydroquinone, hydroquinone monomethyl ether and hindered phenols such as butylated hydroxyanisol, butylated hydroxytoluene (2,6-di-tert-butyl butylphenol and 4methoxyphenol), 4-ethoxyphenol, 3 methoxyphenol, 2-tert-butyl-4 methoxyphenol, and 2,2 methylene-bis-(4-methyl-6-tert-butylphenol).

The 2-cyanoacrylate compositions may contain single or mixtures of plasticizers such as tributyl acetyl citrate, dimethyl sebacate, diethyl sebacate, try-ethyl phosphate, tri-(2ethylhexyl)phosphate, tri-cresyl phosphate, glyceryl triacetate, glyceryl tributyrate, dioctyl adipate, isopropyl myristate, butyl stearate, trioctyl trimellitate, and dioctyl glutarate. The plasticizers may be added to the compositions in proportions of less than 50% w/w of the formulation.

The 2-cyanoacrylate compositions may contain small amounts of dyes like the derivatives of anthracene and other complex structures. Some of these dyes include, without limitation, 1-hydroxy-4-[4-methylphenylamino]-9,10 anthracenedione (D&C violet No. 2), disodium salt of 6-hydroxy-5-[(4-sulfophenyl)axo]-2-naphthalene-sulfonic acid (FD&C Yellow No. 6,), 9-(o-carboxyphenyl)-6-hydroxy-2,4,5,7-tetraiodo-3H-xanthen-3-one disodium salt monohydrate (FD&C Red No. 3), 2-(1,3dihydro-3-oxo-5-sulfo-2-indole-2-ylidine)-2,3-dihydro-3-oxo-1H-indole-5-sulfonic acid disodium salt (FD&C Blue No. 2), and [phthalocyaninato (2)] copper added in proportions of less than 50,000 ppm.

The sterilized cyanoacrylate adhesive compositions of the invention may be packaged in a container made of any suitable material. Suitable materials must be heat stable and resistant up to the sterilization temperature, must provide an adequate barrier to atmospheric moisture and be compatible with the cyanoacrylate monomer or monomers. Materials meeting these requirements include metals and borosilicate type I glass. Suitable metals can include without limitation aluminum, tin, and stainless steel. Metals can have different forms like pouches and tubes. Glass can be used as vials, breakable tubes or any other shape, and contained inside tubes made out of the same material, or combinations or materials including plastics. Particularly preferred materials are aluminum and type I glass. Preferred aluminum tubes comprise a nozzle which is hermetically sealed by a pierceable membrane of aluminum and are filled at their end remote from the nozzle prior to closure of the open end by tight crimping. The glass vials used in this invention, are made out of borosilicate type I glass and sealed with a threaded phenolic cap with a silicone/Teflon septum or sealed with an aluminum crimp cap and a silicone/Teflon septum. In the result, therefore, preferred embodiments of the invention reside in a substantially hermetically sealed aluminum container, e.g. an aluminum tube, containing a sterile 2-cyanoacrylate composition or type I glass vials hermetically sealed with a phenolic threaded cap and a silicone/Teflon septum.

EXAMPLES Example 1 Sample Testing: (Sterility Test Method for all Samples)

The method was tested by first performing the USP bacteriostasis and fungi stasis test on glass vials and aluminum tubes. The sterility test was performed by obtaining spores of Bacillus subtilis var. niger suspended in irrigation water at a concentration of 2.3×10⁺⁸/ml. Aliquots of 0.48 ml of these spores were placed in glass serum bottles, lyophilized and then reconstituted with 50 ml of n-butyl or 2-octylcyanoacrylate compositions to obtain a volume of 50 ml of inoculated spore solution with a concentration of 2×10⁺⁶/ml. These cyanoacrylate spore solutions were used to fill the tubes and vials for the sterilization trials at different temperatures and time and for the non-sterilized (standard biological indicators) control vials and tubes. Each tube and vial was filled with a volume of 0.5 to 0.6 ml of a cyanoacrylate composition that rendered a spore concentration of 2×10⁺⁶/ml. Non-sterilized biological indicators and sterilized spores inoculated samples at different temperatures and time were transferred to a 5% dextrose USP solution, shaken and transferred to soy casein digested broth (SCDB) and incubated at 35-37° C. for at least seven days. A vial of lyophilized spores with no cyanoacrylate was tested for population verification. The vial was transferred to sterile purified water and vortexed for 10 minutes. Serial dilutions of 10⁺⁴, 10⁺⁵, and 10⁺⁶ were plated in duplicate using soy casein digested broth (SCDB) and incubated for 48 hours at 35-37° C. The 10⁺⁶ dilution yielded duplicate plates in the countable range. The final calculations showed there were 6.1×10⁺⁶ CFU/ml, or 3.1×10⁺⁷ CFU/vial.

Polymer Preparation: (Polymer Method for Samples Containing Polymer)

2-OCA polymer was made by adding drop by drop 30 grams of 2-OCA monomer to a blender containing 1000 ml of 0.1% sodium bicarbonate deionized water while swirling. Bicarbonate water with the polymer was vacuum filtered on a Kitasato with a Fisherbrand #Q5 quantitative filter paper, rinsed five times with 500 ml aliquots of deionized water and decanted. The polymer was neutralized with 500 ml of 0.1 N hydrochloric acid. The neutralized polymer was rinsed with three aliquots of 500 ml, decanted, dried in a vacuum oven at 80° C., and after drying was finely ground with a mixer.

Sample Composition Preparation:

The sample of 2-OCA containing polymer was made by mixing 2-octyl cyanoacrylate (stabilized with 100 ppm of SO₂, 1000 ppm of butylated hydroxyanisole) with 3.5% of 2-OCA polymer. The polymer was dissolved in the formulated 2-OCA by heating and mixing in a round glass flask equipped with a paddle shaft and mixer at a temperature no higher than 80° C. and obtaining a viscosity of 567 cp (measured with a Brookfield DV-II at 25° C.). Then, the composition was inoculated with lyophilized Bacillus subtilis spores to produce a minimum concentration of 1×10⁺⁶ which were filled in aluminum tubes and glass type I glass threaded vials. Tubes were sealed by crimping with a Kentex automatic tubes filler and sealer. The glass vials were filled with an Eppendorf automatic pipette and sealed with threaded phenol caps and silicone/Teflon septa. Some inoculated glass and tube samples were not sterilized and were used as positive standard biological indicators to indicate livable spores. The rest of the inoculated and sealed tubes and vials were exposed to the experimental temperatures and time stipulated in the sterilization testing protocol conditions.

Tables #2-3 shows example results.

TABLE #2 2-OCA sterilization example packed in glass vials with pre-sterilization viscosity of 567 cp Sterilization Type of Incubation Number Number of Sterilization time Media temperature samples days of Number of Viscosity @ ° C. minutes 400 ml ° C. tested incubated positives 25° C. sterile 90 240 SCDB 30-35 3 7 1 566 100 120 SCDB 30-35 3 7 0 569 100 180 SCDB 30-35 3 7 0 562 110 60 SCDB 30-35 3 7 0 526 110 120 SCDB 30-35 3 7 0 452 120 60 SCDB 30-35 3 7 0 418 120 90 SCDB 30-35 3 7 0 N/A 130 60 SCDB 30-35 3 7 0 343 130 120 SCDB 30-35 3 7 0 N/A 140 30 SCDB 30-35 3 7 0 110 140 45 SCDB 30-35 3 7 0 N/A Table #2 above shows minimum sterilization temperatures, incubation temperature, incubation time and the results obtained for samples of Bacillus subtilis spores inoculated 2-OCA containing 3.5% 2-OCA polymer (567 cp), 100 ppm SO₂ and 1000 ppm BHA.

TABLE #3 2-OCA sterilization example packed in aluminum tubes with pre-sterilization viscosity of 567 cp Sterilization Type of Incubation Number Number of Sterilization time Media temperature samples days of Number of Viscosity @ ° C. minutes 400 ml ° C. tested incubated positives 25° C. sterile 90 240 SCDB 30-35 3 7 2 565 100 120 SCDB 30-35 3 7 0 566 100 180 SCDB 30-35 3 7 0 570 110 60 SCDB 30-35 3 7 0 526 110 120 SCDB 30-35 3 7 0 435 120 60 SCDB 30-35 3 7 0 405 120 90 SCDB 30-35 3 7 0 N/A 130 60 SCDB 30-35 3 7 0 351 130 120 SCDB 30-35 3 7 0 N/A 140 30 SCDB 30-35 3 7 0 102 140 45 SCDB 30-35 3 7 0 N/A Table #3 above shows minimum sterilization temperatures, incubation temperature, incubation time and the results obtained for samples of Bacillus subtilis spores inoculated 2-OCA containing 3.5% 2-OCA polymer (567 cp), 100 ppm SO₂ and 1000 ppm BHA. Note the sharp drop in the viscosities of the compositions tested and shown in Tables 2 and 3 as temperature passes 110° C. The average viscosity drop from the base viscosity (567 cp) in the last column in each table going from row 4 to row 5 is 14.45%.

Example II Sample Composition Preparation Sample IIA:

A sample of n-butyl cyanoacrylate (n-BCA) with a viscosity of 2.8 cp (measured with a Brookfield DV-II at 25° C.) containing 100 ppm of SO₂ and 1000 ppm of butylated hydroxyanisole (BHA) was prepared for this example. Then, the composition was inoculated with biological indicator standards such as borosilicate spore discs, cotton threads and spore wires with a spore concentration of 1×10⁺⁶ Geobacillus stearothermophilus. The spore inoculated composition was filled in type I glass threaded vials with an Eppendorf automatic pipette and sealed with threaded phenol caps and silicone/Teflon septa. Some inoculated glass vials were not sterilized and were used as positive standard biological indicators to indicate livable spores. The rest of the inoculated sealed vials were exposed to the experimental temperatures and times stipulated in the sterilization testing protocol conditions.

Table #4 shows example results.

TABLE #4 n-BCA monomer sterilization example in glass vials with pre-sterilization viscosity of 2.8 cp Sterilization Type of Incubation Number Number of Sterilization time Media temperature samples days of Number of Viscosity @ 100° C. minutes 400 ml ° C. tested incubated positives 25° C. sterile borosilicate 240 SCDB 55-60 3 7 0 2.9 disc Cotton 240 SCDB 55-60 3 7 0 2.8 threads SS wires 240 SCDB 55-60 3 7 0 2.8 Positive NO SCDB 55-60 3 2 3 2.8 control borosilicate disc Positive NO SCDB 55-60 3 2 3 2.9 Control cotton threads SS wires NO SCDB 55-60 3 2 3 2.8 Table #4 above shows sterilization temperatures, incubation temperature, incubation time and the results obtained for samples of Geobacillus stearothermophilus spores inoculated n-BCA containing, 100 ppm SO₂ and 1000 ppm BHA.

Sample IIB:

A sample of n-butyl cyanoacrylate (n-BCA) with a viscosity of 2.8 cp (measured with a Brookfield DV-II at 25° C.) containing 100 ppm of SO₂ and 1000 ppm of butylated hydroxyanisole (BHA) was prepared for this example. Then, the composition was inoculated with biological indicator standards cotton threads with a spore concentration of 1×10⁺⁶ Bacillus subtilis. The spore inoculated composition was filled in type I glass threaded vials with an Eppendorf automatic pipette and sealed with threaded phenol caps and silicone/Teflon septa. Some inoculated glass vials were not sterilized and were used as positive standard biological indicators to indicate livable spores. The rest of the inoculated sealed vials were exposed to the experimental temperatures and times stipulated in the sterilization testing protocol conditions.

Tables #5 shows example results.

TABLE #5 n-BCA monomer sterilization example in glass vials with pre-sterilization viscosity of 2.8 cp Sterilization Type of Incubation Number Number of Sterilization time Media temperature samples days of Number of Viscosity @ 100° C. minutes 400 ml ° C. tested incubated positives 25° C. sterile Cotton 240 SCDB 55-60 3 7 1 2.8 threads Positive NO SCDB 55-60 3 2 3 2.8 Control cotton threads Table #5 above shows sterilization temperatures, incubation temperature, incubation time and the results obtained for samples of Bacillus subtilis spores inoculated n-BCA containing 100 ppm SO₂ and 1000 ppm BHA. 

1. A cyanoacrylate adhesive composition, comprising: at least one 2-cyanoacrylate monomer; and at least one polymeric thickener in an amount establishing an initial viscosity that will not significantly increase when the composition is sterilized at a temperature no greater than approximately 110° C. for a period of time sufficient to sterilize the composition.
 2. The composition of claim 1, in which: said initial viscosity is in the range of about 400 to about 600 centipoises.
 3. The composition of claim 1, in which: said period of time is no greater than about 120 minutes.
 4. An article of manufacture, comprising: a container packed with a mixture of at least one 2-cyanoacrylate monomer; and at least one polymeric thickener in an amount establishing a viscosity that will not significantly increase when the mixture is sterilized; the container then being sealed; and heated to a temperature of between about 100° C. and about 110° C. for a period of time between about 60 minutes and about 120 minutes.
 5. An article of manufacture, comprising: a container comprised of a material taken from the list of: (a) aluminum, (b) plastic, and (c) glass; packed with a mixture of about 3.5% by weight of polyoctyl-2-cyanoacrylate, about 100 ppm sulfur dioxide, and about 1000 ppm butylated hydroxyanisole (BHA), all dissolved in the balance percentage by weight of octyl-2-cyanoacrylate monomer, then sealed; and the sealed container heated to a temperature of between about 100° C. and about 110° C. for a period of time between about 60 minutes and 120 minutes, establishing a sterile adhesive having a viscosity of in the range of about 400 centipoises to about 600 centipoises. 